Compositions and methods for controlling neuronal excitation

a technology of excitation and composition, applied in the field of composition and method of controlling neuronal excitation, can solve the problems of limited system use, limited clinical application of current optogenetic approaches, and limited prior work in chemical optogenetics to cultured cells, so as to achieve the effect of reducing the functional output of the neuron and increasing the activity of the neuron

Inactive Publication Date: 2016-11-08
THE GENERAL HOSPITAL CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In some embodiments, the activity of the neuron can be increased. In some embodiments, the functional output of the neuron can be decreased. In some embodiments, the neuron can be functionally ablated. In some embodiments, the neuron can be ablated.

Problems solved by technology

Optogenetics has yielded remarkable new insights in cultured cells and in some model organisms, but its use is limited to systems that can be manipulated by transgenesis to express the bacterial opsins.
Therefore, current optogenetic approaches are not applicable in the clinic as they do not provide a means to control endogenous neuronal proteins and neuronal signaling in non-transgenic animals with electromagnetic radiation.
However, virtually all prior work in chemical optogenetics has been limited to cultured cells, tissue slices, and other ex vivo preparations because most existing techniques are not effective in vivo.

Method used

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  • Compositions and methods for controlling neuronal excitation
  • Compositions and methods for controlling neuronal excitation
  • Compositions and methods for controlling neuronal excitation

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification and Characterization of Optovin

[0639]Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity1-14. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Identified herein are small molecules, including optovin, that enable repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. Described herein is the identification of a light-based strate...

example 2

Photo-Sensitive TRPA1 Agonist Treatment

[0728]Dosage combinations of a photo-sensitive TrpA1 agonist as described herein and electromagnetic radiation can be used to induce muscle contractions in mice. Mice can be administered a dose of a photo-sensitive TrpA1 agonist systemically, e.g. orally or via injection, or locally, e.g. by topical application. The photo-sensitive TrpA1 agonist can cross the epidermis and enter muscle tissues or be transported to the muscle tissue systemically. The target muscle can then be exposed to electromagnetic radiation of the appropriate wavelength, i.e. a wavelength that will activate that particular photo-sensitive TrpA1 agonist. The electromagnetic radiation can be directed through the epidermis to reach the neurons in the muscle tissue. Alternatively, the radiation can be generated in or near the muscle tissue, e.g. by an implanted, wirelessly controlled LED. Alternatively, the radiation can be generated by an external or implanted radiation source...

example 3

Development of Optovin-Class Compounds

[0730]To optimize optovin for photochemical control of TrpA1, medicinal chemistry can be used to create a panel of optimized optovin derivatives that permit flexible manipulation of TrpA1 activity. Optimization can focus on developing compounds that are more potent than optovin and compounds that have desirable physicochemical properties, including altered wavelength sensitivity and rapid photoswitching kinetics. Compounds can also be optimized for low in vivo toxicity and tested for conservation across species.

[0731]Additionally, photo-dependent ligands can be developed for additional TRP channels. Compounds can be tested in a panel of cell-based calcium assays to identify compounds that cause photochemical gating of four other TRP channels, TrpC1, TrpV1, TrpC6, and TrpM8. Compounds with activity beyond TrpA1 can be further optimized to generate selective, photoswitchable probes for each of the target TRP channels.

[0732]Iterative cycles of medi...

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Abstract

Embodiments of the technology described herein relate, at least in part, to methods of modulating the activity of a neuron by contacting the neuron with a photo-sensitive TrpA1 agonist and then illuminating the neuron with electromagnetic radiation. Also described herein are photo-sensitive TrpA1 agonists.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a 35 U.S.C. §371 National Phase Entry Application of International Application No. PCT / US2012 / 042151 filed Jun. 13, 2012, which designates the U.S., and which claims benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 61 / 496,178 filed Jun. 13, 2011, the contents of each of which are incorporated herein by reference in their entireties.GOVERNMENT SUPPORT[0002]This invention was made with federal funding under Grant Nos. K01MH091449, MH086867, MH085205, HL109004, and DA026982 awarded by the National Institutes of Health and Grant Nos. R01NS060725, R01NS067688, and F31NS068038 awarded by the National Institute of Neurological Disorders and Stroke. The U.S. government has certain rights in the invention.TECHNICAL FIELD[0003]The technology described herein relates to methods for modulating the activity of neurons using photo-sensitive compounds as described herein.SEQUENCE LISTING[0004]The instant applicatio...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/4439A61K41/00A61K31/427A61N5/06A61K31/426A61K31/4406
CPCA61K31/4439A61K31/426A61K31/427A61K31/4406A61K41/00A61N5/062A61N5/0622A61N2005/0661A61N2005/0663A61P43/00
Inventor PETERSON, RANDALLCHEUNG, CHUNG YAN J.KOKEL, DAVID
Owner THE GENERAL HOSPITAL CORP
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